Dr. M. Brandon Westover is a practicing Neurologist and clinical electroencephalographer at Massachusetts General Hospital (MGH), whose goal is to become an independent investigator with expertise in biomedical signal processing and pharmacodynamics as they relate to sedation and analgesia in critically ill patients. His career development plan leverages the resources of a world-class environment by bringing together an out-standing team of investigators centered at a leading academic institution in Boston, Massachusetts General Hospital. Dr. Westover has already obtained preliminary results demonstrating the feasibility of a research plan that combines pharmacokinetic/pharmacodynamic (PK/PD) modeling with real-time automated processing of EEG and other physiological signals to quantitatively monitor and provide closed-loop control of sedation and analgesia in ICU patients. Under the mentorship of Dr. Emery Brown, and co-Mentors Dr. Sydney Cash and Dr. Patrick Purdon, Dr. Westover proposes: 1) To determine which features of the EEG and other physiological signals systematically relate with levels of sedation and analgesia in ICU patients, 2) To determine the full range and variability of pharmacodynamic responses in ICU patients receiving combinations of two specific intravenous sedative-analgesic medications, namely dexmedetomidine and remifentanil, and 3) To investigate whether a closed-loop drug delivery system, which integrates knowledge about population-level PK/PD characteristics of dexmedetomidine and remifentanil with real-time physiological feedback about an individual's level of pain and level of consciousness, can achieve more precise control of sedation-analgesia than is possible under current clinical practices. The overall goal is to develop an understanding of how to objectively and quantitatively monitor pain and sedation in the ICU setting, and to use this understanding to reduce the now pervasive problem of morbidity due to over- and under-dosing of sedative-analgesic drugs. Bringing together cutting-edge technology and a team with relevant expertise, this project will open new avenues for optimizing care and improving outcomes for a broad range of ICU patients. This well-defined patient-oriented research proposal, in concert with mentorship and a structured didactic curriculum, will provide Dr. Westover with the skills that are essential to develop an independent career in clinical neurophysiological research at the cutting edge of science.